Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome

• Published in: Blood Vol. 143; no. 15; pp. 1496 - 1512
• Main Authors: Vadivel, Chella Krishna, Willerslev-Olsen, Andreas, Namini, Martin R. J., Zeng, Ziao, Yan, Lang, Danielsen, Maria, Gluud, Maria, Pallesen, Emil M. H., Wojewoda, Karolina, Osmancevic, Amra, Hedebo, Signe, Chang, Yun-Tsan, Lindahl, Lise M., Koralov, Sergei B., Geskin, Larisa J., Bates, Susan E., Iversen, Lars, Litman, Thomas, Bech, Rikke, Wobser, Marion, Guenova, Emmanuella, Kamstrup, Maria R., Ødum, Niels, Buus, Terkild B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2024; The American Society of Hematology
• Subjects: Lymphoid Neoplasia
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023021671

•Enterotoxins from S aureus bacteria induce drug resistance in primary malignant T cells in SS.•Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance. [Display omitted] Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus–specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus. Patients with Sézary syndrome (SS) are prone to Staphylococcus aureus infections and have treatment resistance which leads to poor prognosis. Vadivel and colleagues link these observations, suggesting that staphylococcal enterotoxins (SE) induce drug resistance in SS T cells through induction of several T-cell signaling pathways. Treatment with antibacterials as well as downstream mediators triggered by SE abrogate drug resistance, suggesting that antistaphylococcal antibiotics might improve outcomes of SS-directed therapy.